The gamma chain gene of the interleukin-2 receptor (IL2RG) is the disease gene for X-linked severe combined immunodeficiency (XSCID). This gene defect occurs in 1 in 10,000 to 100,000 births. Males with XSCID generally die of infections in the first year of life unless they are rescued by bone marrow transplantation. New mutations account for a substantial proportion of cases. Detection of IL2RG mutations in XSCID males allows: i) definition of clinical features and long-term follow- up of XSCID; ii) study of specific mutations with regard to frequency and clinical severity; iii) study of functional characteristics of defective gamma chain protein encoded by mutated IL2RG from XSCID patients; iv) participation in the evolving management of SCID families, including devising and performing carrier and prenatal testing; v) examining psychologic impact of XSCID on families and their utilization of genetic services; and vi) planning new therapeutic approaches. Research efforts have been aimed at mutation detection by single strand conformation polymorphism, dideoxy fingerprinting and sequencing. A worldwide database of mutations created here, IL2RGbase, currently lists over 170 independent mutations, two thirds of which were found in this laboratory. Unique genetic features including germ line mosaicism, a branch point A mutation and 5 mutation hot spots have been found. Prenatal monitoring of at-risk pregnancies has allowed for implementation of neonatal bone marrow transplantation and utero transplantation. Our pool of XSCID affected subjects with proven mutations will allow us to choose and have access to appropriate subsets of XSCID patients likely to benefit from retroviral gene therapy.